{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:47:57Z","timestamp":1776872877070,"version":"3.51.2"},"reference-count":26,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp;amp; Biodiversity"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Diabetic foot ulcers (DFUs) exhibit impaired healing due to disrupted macrophage polarization, wherein persistent hyperglycemia inhibits the critical M1\u2010to\u2010M2 phenotypic transition, sustaining a pro\u2010inflammatory microenvironment. This investigation elucidates the therapeutic potential of L\u2010shikonin (L\u2010SK), a bioactive phytochemical derived from comfrey with established immunomodulatory properties. In a streptozotocin\u2010induced diabetic murine model, L\u2010SK treatment significantly enhanced wound closure through coordinated anti\u2010inflammatory effects (downregulation of CD86 and tumor necrosis factor\u2010\u03b1) and pro\u2010regenerative outcomes (increased collagen deposition and CD31\u2010mediated angiogenesis). At the molecular level, L\u2010SK administration facilitated macrophage polarization towards the regenerative M2 phenotype (upregulated CD163 expression) while activating the pivotal Janus Kinase\/phosphatidylinositol\u20103\u2010kinase\/protein kinase B\/vascular endothelial growth factor (JAK\/PI3K\/AKT\/VEGF) signaling cascade, as evidenced by enhanced phosphorylation of AKT and PI3K alongside elevated VEGF production. Complementary in vitro studies using human monocytic leukemia cells\u2010derived macrophages confirmed these mechanistic findings, demonstrating consistent modulation of macrophage differentiation markers and secretory profiles. These results position L\u2010SK as a multifaceted therapeutic agent capable of concurrently addressing the immunological and vascular deficiencies characteristic of DFUs, through its dual capacity for macrophage phenotype reprogramming and angiogenic pathway activation. The study provides compelling preclinical evidence for L\u2010SK's potential application in diabetic wound management strategies.<\/jats:p>","DOI":"10.1002\/cbdv.202501224","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T20:20:45Z","timestamp":1755548445000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the Anti\u2010inflammatory Molecular Mechanism of L\u2010shikonin in Promoting Diabetic Wound Healing by Modulating the Janus Kinase\/Phosphatidylinositol\u20103\u2010kinase\/Protein Kinase B\/Vascular Endothelial Growth Factor Pathway Based on Network Pharmacology"],"prefix":"10.1002","volume":"22","author":[{"given":"Kun","family":"Li","sequence":"first","affiliation":[{"name":"College of Chemistry and Chemical Engineering Liaoning Normal University  Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering Liaoning Normal University  Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiantian","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering Liaoning Normal University  Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijie","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering Liaoning Normal University  Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunpeng","family":"Diao","sequence":"additional","affiliation":[{"name":"College of Pharmacy Dalian Medical University  Dalian China"},{"name":"Dalian Anti\u2010Infective Traditional Chinese Medicine Development Engineering Technology Research Center  China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-5723","authenticated-orcid":false,"given":"Shuyuan","family":"Fan","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering Liaoning Normal University  Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901263"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2024.111446"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2021.103904"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0264572"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S449565"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59643"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2021.05.006"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijnss.2020.05.008"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0b013e328347970b"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.014597"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16121543"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.2.1146"},{"key":"e_1_2_10_14_1","first-page":"7","article-title":"Advances in Studies on Medicinal Radix Arnebiae Seu Lithospermi","volume":"34","author":"Feng G. 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